Acquired immune deficiency syndrome (AIDS) is recognized as one of the greatest health threats facing modern medicine. Treatments for human immunodeficiency virus (HIV)-infected individuals as well as the development of vaccines to protect against infection are urgently needed. One difficulty has been in eliciting neutralizing antibodies to the virus.
The HIV-1 envelope glycoproteins (gp120-gp41), which mediate receptor binding and entry, are the major targets for neutralizing antibodies. Although the envelope glycoproteins are immunogenic and induce a variety of antibodies, the neutralizing antibodies that are induced are strain-specific, and the majority of the immune response is diverted to non-neutralizing determinants (Weiss, R. A., et al., Nature, 316 (6023): 69-72, 1985; Wyatt, R. and J. Sodroski, Science, 280 (5371): 1884-1888, 1998). Broadly neutralizing antibodies have been isolated only rarely from natural HIV infection, as only five broadly-neutralizing antibodies have been identified to date. Three are gp41-directed (2F5, 4E10 and Z13) and the other two (b12 and 2G12) are gp120-directed. The three gp41 neutralizing antibodies recognize the membrane proximal region (MPR) of the HIV-1 gp41 glycoprotein. The MPR region includes a series of amino acids that lie on the HIV vsurface, just before gp41 crosses the viral membrane. The MPR is highly hydrophobic (50% of residues are hydrophobic), and is highly conserved across many HIV clades (Zwick, M. B., et al., J Virol, 75 (22): 10892-10905, 2001). Recently the hydrophobic context of MPR and the presence of lipid membrane were shown to be important for the optimal binding of 2F5 and 4E10 antibodies (Ofek, G., et al., J Virol, 78 (19): 10724-37, 2004).
To date, immunization with conserved membrane proximal elements or the core 2F5 epitope in a number of contexts has failed to elicit broadly neutralizing antibodies (Coeffier, E., et al., Vaccine, 19 (7-8): 684-693, 2000; Eckhart, L., et al., J Gen Virol, 77 (Pt 9): 2001-2008, 1996; Ernst, W., et al., Nucleic Acids Res, 26 (7): 1718-1723, 1998; Ho, J., et al., Vaccine, 20 (7-8): 1169-1180, 2002; Liang, X., et al., Epitop Vaccine, 17 (22): 2862-2872, 1999; Liao, M., et al., Peptides, 21 (4): 463-468, 2000; Xiao, Y., et al., Immunol Invest, 29 (1): 41-50, 2000). Thus, there remains a need to identify HIV antigens that can be used to induce a protective immune response.